title: Impaired L-arginine uptake but not arginase contributes to endothelial dysfunction in rats with chronic kidney disease.
abstract: Reduced nitric oxide bioavailability contributes to increased cardiovascular disease risk in patients with chronic kidney disease (CKD). Arginase has been implicated as a potential therapeutic target to treat vascular dysfunction by improving substrate availability for endothelial nitric oxide synthase. The purpose of this study was to determine if arginase contributes to endothelial dysfunction in the 5/6 ablation infarction (AI) rat model of CKD. Endothelium-dependent relaxation of aortic rings to acetylcholine was significantly impaired in AI animals versus sham after 8 weeks and was not improved by arginase inhibition (S-(2-Boronoethyl)-L-cysteine hydrochloride) alone or in combination with L-arginine. Additionally, scavenging of superoxide (Tempol, Tempol + L-arginine, Tempol + L-arginine + S-(2-Boronoethyl)-L-cysteine hydrochloride) was not effective, suggesting that a mechanism independent of oxidative stress contributes to endothelium-dependent relaxation in moderate to severe CKD. Aortic uptake of radiolabeled L-arginine was attenuated in AI animals and was associated with a reduced expression of the L-arginine transporter CAT-1. These data suggest that arginase does not contribute to endothelial dysfunction in CKD; however, impaired L-arginine transport may play an important role in diminishing substrate availability for nitric oxide production leading to endothelial dysfunction.
authors.affiliation: Departments of *Kinesiology and Applied Physiology; †Biological Sciences; and ‡Behavioral Health and Nutrition, University of Delaware, Newark, DE.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Martens
authors.forename: James M
authors.initials: JM
authors.lastname: Kuczmarski
authors.forename: Shannon
authors.initials: S
authors.lastname: Lennon-Edwards
authors.forename: David G
authors.initials: DG
authors.lastname: Edwards
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism*; D001693:Biological Transport, Active; D001794:Blood Pressure / Q000502:physiology; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D003404:Creatinine / Q000097:blood; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007537:Isometric Contraction; D007668:Kidney / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000652:urine; D009929:Organ Size / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology*; D014527:Uric Acid
chemical_list: D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D014527:Uric Acid; D009569:Nitric Oxide; D001120:Arginine; D003404:Creatinine; D001119:Arginase